Preparation and Medical Use of Triazenes

ABSTRACT

The present invention relates to a novel method for preparing triazenes. Further, the invention relates to novel triazenes and the use of N 2 O for preparing a compound comprising a triazene group. Further, the invention relates to the use of the novel triazenes as a medicament, in particular in the treatment of cancer.

The present invention relates to a novel method for preparing triazenes.Further, the invention relates to novel triazenes and the use of N₂O forpreparing a compound comprising a triazene group. Further, the inventionrelates to the use of the novel triazenes as a medicament, in particularin the treatment of cancer.

Triazenes are valuable compounds in organic chemistry and numerousapplications have been reported. For example, D. B. Kimball and M. M.Haley consider triazenes as “a versatile tool in organic synthesis”(Angew. Chem. Int. Ed. 41, 3338 (2002)). Triazenes have been used asmultifunctional linkers in solid-phase synthesis, as removable directinggroups for C—H activation, as protecting groups during the synthesis ofcomplex natural products and of shape-persistent phenylacetylene-basedsystems, and for the controlled desaturation of unactivated aliphaticcompounds.

In addition to their synthetic utility, triazenes have gained importancebecause of their biological activity. Inter alia, triazenes have beeninvestigated extensively as potential antitumor drugs, and the triazenesdacarbazine and temozolomide are currently used in the clinic for thetreatment of cancer.

Trisubstituted triazenes can be obtained by different synthetic routes.

H. Zollinger, Diazo Chemistry I; Wiley-VCH, Weinheim, pp. 385-404 (1994)relates to the formation and reactions of triazenes. A frequently usedmethod for the synthesis of trisubstituted triazenes relies on thecoupling of diazonium salts with secondary amines. In particular, anaromatic diazonium compound is allowed to react with a secondary aminecontaining alkyl, aryl or heteroaryl substituents.

A more specific method is described by D. H. Sieh, D. J. Wilbur, C. J.Michejda, J. Am. Chem. Soc. 102, 3883 (1980). An azide, such as benzylazide or n-butyl azide, is allowed to react with a Grignard reagent oran organolithium compound, followed by alkylation with organohalides,such as methyl iodide, to obtain two constitutional isomers of theresulting triazenes.

Triazenes with alkyl or aryl substituents in position 1 are available bythe known synthetic routes. The pharmacological research has focused onthe more stable aromatic triazenes like described in EP 2 55 075 A1.

Certain triazenes, for example trisubstituted triazenes with alkenyl oralkynyl groups in position 1, are not easily accessible by the abovemethods due to the high instability of the required starting materials.1-Azido-1-alkynes, for example, would decompose at low temperatures andthe first spectroscopic characterization of such a compound was onlyachieved recently. Diazonium salts of alkenes and alkynes are likewiseunstable.

Due to the numerous applications of substituted triazenes, in particularthe possible use as a pharmaceutical active ingredient, there is still aneed for new methods of preparing triazenes, in particulartrisubstituted triazenes with alkenyl or alkynyl groups in position 1.

Hence, it was an object of the present invention to overcome theabove-mentioned disadvantages.

It was an object of the present invention to provide a process forpreparing triazenes with a high yield and/or a high grade ofselectivity.

It was a further object of the invention to provide a method forpreparing substituted triazenes wherein the method can be appliedindependently from the type of substituents. In particular, a method forpreparing triazenes with specific substituents, preferably withnon-aromatic substituents such as 1-alkenyl and 1-alkynyl groups, shouldbe provided.

Thus, the above objectives are unexpectedly solved by the provision of anew synthetic approach for preparing substituted triazenes.

In said new approach, a compound according to Formula (II) is reactedwith a compound of Formula (III) for preparing a substituted triazene.

Hence, a subject of the present invention is a method for preparing atriazene according to Formula (I)

by reacting a compound according to Formula (II)

R¹R²N(N₂O)M¹  Formula (II)

with a compound of Formula (III)

R³M²  Formula (III)

whereinR¹ and R² independently are an organic residueR³ is an organic residue,M¹ is a metal compound, preferably selected from Li, Na, K, and M² is ametal compound, preferably selected from Li, Na, K, MgCl, MgBr, MgI,ZnCl, ZnBr, ZnI, ZnR^(3′), and AlR^(3′)R^(3″), wherein R^(3′) and R^(3″)are independently an organic residue.

It was found that the present process allows advantageous yield andselectivity of the resulting triazenes. Further, simple reactionconditions can be applied and the usage of potentially hazardous andexplosive diazonium salts can be advantageously avoided. Additionally,besides alkyl and aryl substituted triazines, also 1-alkenyl and1-alkynyl triazines are easily accessible.

Another subject of the invention is the use of N₂O for preparing acompound comprising a triazene group.

The invention further relates to a compound according to Formula (I)wherein R³ is —C≡C—R⁵, wherein R⁵ is an organic residue; or R³ is—R⁶C═CR⁷R⁸, wherein R⁶, R⁷, R⁸ are independently an organic residue, andwith the proviso that the C═C-bond is not part of an aromatic system.Another subject is a compound according to Formula (I) for use as amedicament, in particular for use in the treatment of cancer.

During the processes described in the present invention, a compoundaccording to Formula (II) can be an important intermediate. Hence, thepresent invention is directed to a compound according to Formula (II)and a method for preparing said compound.

DETAILED DESCRIPTION OF THE INVENTION

The present method for preparing a triazene according to Formula (I)

comprises reacting a compound according to Formula (II) with a compoundof Formula (III)whereinR¹ and R² independently are an organic residueR³ is an organic residue,M¹ is a metal compound, preferably selected from Li, Na, K, andM² is a metal compound, preferably selected from Li, Na, K, MgCl, MgBr,MgI, ZnCl, ZnBr, ZnI, ZnR^(3′), and Al R^(3′)R^(3″), wherein R^(3′) andR^(3″) are independently an organic residue.

“Organic residue” generally refers any residue known in organicchemistry. Preferably, the skeleton of the organic residue containspredominately carbon atoms, nitrogen atoms and/or oxygen.

In a preferred embodiment, R¹ and R² can be independently a substitutedor unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted alkyl group with 1 to 16carbon atoms, a substituted or unsubstituted cyclic alkyl group with 3to 12 carbon atoms, a substituted or unsubstituted cyclic alkenyl groupwith 3 to 12 carbon atoms, a substituted or unsubstituted alkenyl groupwith 2 to 16 carbon atoms, or a substituted or unsubstituted alkynylgroup with 2 to 16 carbon atoms, wherein in the substituted orunsubstituted alkyl group with 1 to 16 carbon atoms, the substituted orunsubstituted cyclic alkyl group with 3 to 12 carbon atoms, thesubstituted or unsubstituted cyclic alkyl group with 3 to 12 carbonatoms, the substituted or unsubstituted alkenyl group with 2 to 12carbon atoms, or the substituted or unsubstituted alkynyl group with 2to 16 carbon atoms one or more —CH₂— group(s) can be substituted by a—O—, —S—, —NR⁴—, or SiR⁴R^(4′) to form an ether, a thioether, asecondary or tertiary amine, or a silylether and wherein R⁴ and R^(4′)are independently hydrogen, an alkyl group with 1 to 6 carbon atoms or acyclic alkyl group with 3 to 6 carbon atoms or wherein R¹ and R²together with the nitrogen to which R¹ and R² are attached form a heterocycle with 3 to 7 carbon atoms.

An unsubstituted aryl group refers to a residue with an aromaticskeletal structure, wherein the ring atoms of the aromatic skeletalstructure are carbon atoms.

Examples for aryl groups are phenyl, biphenyl, triphenyl, tetraphenyl,pentaphenyl, hexaphenyl, heptaphenyl, naphthyl, binaphthyl, ternapthyl,tetrahydronaphthyl, anthranyl, phenantranyl, pentacenyl, azulenyl,fluorenyl, indanyl, phenalenyl, acenaphthyl, acephenantrylenylaceantrylenyl, pentalenyl, indyl, pyryl, chrysenyl, naphthacenyl,perylenyl, picenyl, rubincenyl, coronenyl, pyranthrenyl, ovalenyl,hexacenyl, and heptacenyl. Preferred are phenyl, biphenyl and naphthyl,more preferably phenyl and naphthyl, in particular phenyl.

An unsubstituted heteroaryl group refers to a residue with an aromaticskeletal structure, wherein one or more of the ring atoms of thearomatic skeletal structure are not carbon atoms but hetero atoms suchas nitrogen, oxygen, sulphur and/or phosphor.

Examples for heteroaryl groups are pyrryl, pyrrazolyl, imidazolyl,triazolyl, furyl, isooxalyl, oxalyl, oxadiazolyl, thienyl, isothiazolyl,thiazolyl, thiadiazalyl, tetrazolyl, pyridyl, pyrazidyl, pyrazyl,pyrimidyl, triazolyl, indolyl, isoindolyl, benzofuranyl, benzothienyl,benzimidazyl, indazolyl, quinolinyl, isoquinolin, cinnolinyl,quinaxolinyl quinoxalinyl, triazinyl, tetrazinyl, acridinyl, purinyl,and pteridinyl.

In another preferred embodiment, the aryl group or hetero aryl group canbear one or more substituents. Examples for substituents areunsubstituted or substituted alkyl groups with 1 to 6 carbon atoms,unsubstituted or substituted alkoxy groups with 1 to 6 carbon atoms,aryloxy groups, optionally protected amines, optionally protectedmonoalkyl amines, optionally protected monoarylamines, dialkylamines,diarylamines, silyl ethers, halogens or optionally protected hydroxylgroups.

Protection groups for amines or monosubstituted amines are for exampleBoc (tert-butyloxycarbonyl), Z or Cbz (benzyloxycarbonyl), benzyl,benzhydryl, and Fmoc (fluorenylmethylenoxycarbonyl).

Protection groups for hydroxyl groups are for example esters, such asbenzoic acid esters or pivalic acid esters, and trisubstitutedsilylethers, such as trimethylsilylether, triethylsilylether,tert-butyldimethylsilylether and tert-butyl diphenylsilylether.

In a preferred embodiment, R¹ and R² are independently a substituted orunsubstituted alkyl group with 1 to 16 carbon atoms, a substituted orunsubstituted cyclic alkyl group with 3 to 12 carbon atoms wherein oneor more of the —CH₂— group(s) can be substituted by —O—, —S— or —NR⁴—,to form an ether, a thioether or a tertiary amine, and wherein R⁴ is analkyl group with 1 to 6 carbon atoms or a cyclic alkyl group with 3 to 6carbon atoms.

A substituted alkyl or cyclic alkyl group is an alkyl or cyclic alkylgroup substituted by a further group. Examples of substituents arefurther alkyl, alkenyl, alkynyl, halogen, alkoxy, aryloxy groups,optionally protected amines, optionally protected monoalkyl amines,optionally protected monoarylamines, dialkylamines, diarylamines, silylethers, halogens or optionally protected hydroxyl groups, esters andamides of carboxylic acids, unsubstituted and substituted aryl groups,and unsubstituted and substituted hetero aryl groups.

It is preferred that R¹ and R² are equal. Alternatively preferred R¹does not correspond to R².

In a preferred embodiment, R¹ and R² are independently an alkyl groupwith 1 to 6 carbon atoms, more preferably with 1 to 4 carbon atoms or acyclic alkyl group with 3 to 8 carbon atoms, preferably 3 to 6 carbonatoms.

Alkyl groups with 1 to 6 carbon atoms can for example include methyl,ethyl, propyl, isopropyl, butyl, isobutyl, and tert.-butyl, pentyl,2-pentyl, 3-pentyl, hexyl, 2-hexyl and 3-hexyl.

Preferred are isopropyl, isobutyl, tert-butyl, pentyl, 2-pentyl,3-pentyl, hexyl, 2-hexyl and 3-hexyl, in particular isopropyl. In apreferred embodiment methyl is particularly preferred. In a preferredembodiment ethyl is particularly preferred.

Cyclic alkyl groups with 3 to 8 carbon atoms include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl,preferably cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl, morepreferably cyclopentyl and cyclohexyl.

It is preferred that R¹ and R² both are not ethyl. Further, R¹ and/or R²do preferably not contain an acyl group.

In an alternative embodiment, R¹ and R² together with the nitrogen towhich R¹ and R² are attached can form a hetero cycle with 3 to 7 carbonatoms. It is preferred that a hetero cycle with nitrogen (being part ofthe triazene) and 4 or 5 carbon atoms is formed.

R³ can preferably be a substituted or unsubstituted aryl group, or asubstituted or unsubstituted hetero aryl group, or a substituted orunsubstituted alkyl group with 1 to 16 carbon atoms, a substituted orunsubstituted cyclic alkyl group with 3 to 12 carbon atoms, asubstituted or unsubstituted alkenyl group with 2 to 16 carbon atoms, ora substituted or unsubstituted alkynyl group with 2 to 16 carbon atoms,wherein in the substituted or unsubstituted alkyl group with 1 to 16carbon atoms, the substituted or unsubstituted cyclic alkyl group with 3to 12 carbon atoms, the substituted or unsubstituted cyclic alkyl groupwith 3 to 12 carbon atoms, the substituted or unsubstituted alkenylgroup with 2 to 12 carbon atoms, or the substituted or unsubstitutedalkynyl group with 2 to 16 carbon atoms, one or more —CH₂— group(s) canbe substituted by a —O—, —S—, —NR⁴— or SiR⁴R⁴, to form an ether, athioether, a secondary or tertiary amine, or a silylether and wherein R⁴and R^(4′) are independently hydrogen, an alkyl group with 1 to 6 carbonatoms or a cyclic alkyl group with 3 to 6 carbon atoms.

For R^(3′) and R^(3″), the same explanations as above for R³ apply. Itis not obligatory that R³, R^(3′) and R^(3″) are the same specificgroup. For example, R³ can be phenyl, while R^(3′) is ethyl and R^(3′)is propyl. For example, a compound according to Formula (III) can be(Ph)₂Zn or PhZnEt. It is preferred that R³, R^(3′) and R^(3″) are thesame group.

In a preferred embodiment of the invention the triazene according toFormula (I) is a trisubstituted triazene; i.e. R¹, R² and R³ are nothydrogen.

Generally, M¹ is a metal compound. A metal compound can be a compoundwhich contains at least one element being a member of the alkaline metalgroup, the alkaline earth metal group, the transition metal group, thelanthanide group, the actinide group, the metalloid group such as boronand silicon, or the post transition metal group comprising aluminium.The metal compound can be present as an organometallic compound.

Generally, the metal compound can be present in any suitable form, e.g.in any suitable oxidation state. It is preferred that the metal compoundis present in form of an element or in the form of a positive ion. Thision may form the counter ion to the negatively charged residue accordingto Formula (II).

In a preferred embodiment, M¹ is a member of the alkaline metal group orthe alkaline earth metal group, preferably the alkaline metal group.More preferably, M¹ is selected from Li, Na and K, more preferably Liand Na, in particular Li.

Generally, M² and is also a metal compound as described above for M¹. Itis preferred that the metal compound M² is present as a (partially)positively charged compound bonded or associated to the negativelycharged organic residue R³ according to Formula (III).

In a preferred embodiment the compound according to Formula (III) formsan organometallic compound, such as an organomagnesium compound(Grignard compound) or an organozinc compound, preferably anorganomagnesium compound. It is preferred that M² is MgCl, MgBr, or MgI,especially MgCl and MgBr.

Alternatively, M² is a member of the alkaline metal group, the alkalineearth metal group, preferably the alkaline metal group. More preferablyM² is selected from Li, Na and K, more preferably Li and Na, inparticular Li.

According to the present method, a compound according to Formula (II) isreacted with a compound according to Formula (III) to give a triazeneaccording to Formula (I).

The compound according to Formula (III) can be obtained, for example, bymixing magnesium with a non-protic organic solvent free from water and acompound composed of organic residue R³ bonded to a halogen such aschloride, bromide or iodide. Suitable solvents are, for example, etherssuch as diethyl ether or tetrahydrofuran. Further, the reaction canpreferably be carried out under an inert gas atmosphere.

Alternatively, in case of R³ being a terminal alkynyl residue, acompound according to Formula (III) can be obtained by reacting therespective alkyne with a Grignard reagent, for example an alkylmagnesiumhalogenide such as ethylmagnesium chloride, under the release of thecorresponding alkyl such as ethane. For this purpose, a solution of therespective alkyne can be provided in a non-protic organic solvent freefrom water and the alkylmagnesium halogenide, preferably as a solutionor suspension in the same solvent, can be added. Suitable solvents are,for example, ethers such as diethyl ether or tetrahydrofuran, inparticular tetrahydrofuran. Further, the reaction can preferably becarried under an inert gas atmosphere. Preferably, the reaction can becarried out at room temperature, i.e. 23° C. After the completion of theaddition of the alkylmagnesium halogenide, the reaction can preferablybe warmed to 50° C. for about 1 hour to complete the reaction.

In a preferred embodiment of the present method, a solution orsuspension of a compound according to Formula (II) in a first non-proticsolvent—preferably essentially free of water—is provided, preferablyunder an atmosphere of an inert gas. Suitable first non-protic solventscan be alkanes such as pentane, hexane or heptane, cyclic alkanes suchas cyclic pentanes or cyclic hexanes, and ethers such diethyl ether,tert-butyl methyl ether or tetrahydrofuran. To said solution/suspensiona compound according to Formula (III), which can be dissolved,preferably completely dissolved, in a second non-protic solvent freefrom water, is added. The second solvent can be the same as the firstsolvent or different to the first solvent. Preferably, ethers suchdiethyl ether, tert-butyl methyl ether or tetrahydrofuran are used assecond solvent.

The step of reacting the compound according to Formula (II) with acompound according to Formula (III) to give a compound according toFormula (I) can be preferably carried out at increased temperatures,preferably between 25° C. to 65° C., more preferably between 30° C. and55° C. It is further preferred that the temperature is elevated afterthe addition, preferably the complete addition, of the solution of acompound according to Formula (III) to the solution/dispersion ofcompound according to Formula (II). Generally, the reaction time can bebetween 10 and 360 min, preferably between 60 and 240 minutes. Thereaction can be carried out between 30° C. and 70° C., preferablybetween 40° C. and 60° C.

In a preferred embodiment, the ratio of the compound according toFormula (II) to the compound according to Formula (III) is from 1:1 to1:3, preferably from 1:1.2 to 1:2.5, more preferably from 1:1.4 to1:2.2, in particular from 1:1.5 to 1:2.

Preferably, the compound according to Formula (II)

R¹R²N(N₂O)M¹  Formula (II)

is prepared by reacting a compound according to Formula (IV)

with nitrous oxide.

The above reaction involves nitrous oxide which is also known as‘laughing gas’.

This name results from the euphoric effect in case of inhaling the gas.Nitrous oxide is represented by the formula N₂O. It is reported to havea dipole moment of 0.16083 D (5.365·10⁻³¹ C·m). Inter alia, nitrousoxide is used for its anesthetic and analgesic effects in surgery anddentistry. However, nitrous oxide is rarely used in synthetic organicchemistry. Chemical reactions with N₂O typically proceed by oxygen atomtransfer and liberation of nitrogen (N₂). In contrast, there are veryfew examples about the utilization of nitrous oxide as nitrogen donor,in particular in the context of synthetic organic chemistry.

A compound according to Formula (IV) can, for example, be obtained byreacting the corresponding amine (R¹R²NH) with the respective alkalinemetal. Alternatively the corresponding amine (R¹R²NH) can be reactedwith an organometallic compound such as buthyllithium (BuLi) orphenyllithium (PhLi).

It is preferred that a compound according to Formula (IV) is dissolved,preferably completely dissolved, in a non-protic solvent, which ispreferably essentially free from water. Suitable solvents are, forexample, ethers such as diethyl ether or tetrahydrofuran. Further, thesolution of a compound according to Formula (IV) is preferably stirredunder a nitrous oxide atmosphere. Alternatively preferred, nitrous oxidecan be fed into a solution of a compound according to Formula (IV).

The reaction of nitrous oxide with a compound according to Formula (IV)is preferably carried out at temperatures of −10° C. to 50° C.,preferably of 5° C. to 40° C., more preferably of 15° C. to 35° C., inparticular of 20 to 27° C. Further, completion of the reaction takespreferably from 0.5 to 12 hours, more preferably from 1 to 9 hours,especially from 2 to 6 hours.

The compound according to Formula (II) can optionally precipitate fromthe non-protic solvent, preferably in form of a colourless or whitesolid. Further, said compound can optionally be isolated, for example byfiltration, washed with non-protic solvent, for example tetrahydrofurandried under reduced pressure.

Alternatively, after completion of the reaction of nitrous oxide with acompound according to Formula (IV) in a non-protic solvent, theresulting compound according to Formula (II) in the non-protic solventcan preferably be further reacted without isolation of the compoundaccording to Formula (II). For this purpose, nitrous oxide canoptionally be replaced by an inert gas after the completion of thereaction. Examples for such inert gases are nitrogen or argon.

In one embodiment, a triazene according to Formula (I) can be obtainedby reacting a compound according to Formula (IV) with nitrous oxide anda compound according to Formula (III). This reaction can be conducted asa so called “one-pot-reaction”. For this purpose, a compound accordingto Formula (III) and a compound according to Formula (IV) can bedissolved, preferably completely dissolved, e.g. in a non-protic organicsolvent, preferably essentially free from water, or a mixture of suchsolvents and allowed to react with nitrous oxide. Suitable non-proticsolvents correspond to the non-protic solvents free from water describedabove. Tetrahydrofuran can be used in particular.

Optionally a compound according to Formula (II) is obtained in theabove-mentioned manner and subsequently the residual nitrous oxide isremoved/substituted. Subsequently, the compound according to Formula(II) is reacted with a compound according to Formula (III) in a manneras described above to obtain a triazene according to Formula (I).

A further subject of the invention is the use of N₂O for preparing acompound comprising a triazene group. In a preferred embodiment, N₂O isused for preparing a compound according to Formula(e) (I) and/or (II).

Generally, the use of N₂O can be carried out as described in the abovemethods. Further, all explanations given above or below with regard tothe compounds of the present invention or with regard to the process ofthe present invention also relate to the use of the present invention.For example, as illustrated above the process of the present inventionis particularly preferred for producing trisubstituted triazenes. Hence,N₂O is preferably used for preparing trisubstituted triazenes accordingto Formula (I).

It was found that nitrous oxide mediates the coupling of compoundsaccording to Formula (IV) and compounds according to Formula (III) whileserving as nitrogen donor. Despite the very inert character of nitrousoxide, the reactions can be performed in solution under mild condition.

Examples of triazines containing aromatic residues prepared by thepresent process are

An advantage of the present process is that the potentially hazardousaryl diazonium salts can be avoided.

Another subject of the present invention is a compound according toFormula (I),

whereinR¹ and R² independently are an organic residue, andR³ is —C≡C—R⁵, wherein R⁵ is an organic residue; orR³ is —R⁶C═CR⁷R⁸, wherein R⁶, R⁷, R⁸ are independently an organicresidue and with the proviso that the C═C-bond is not part of anaromatic system.

In a preferred embodiment of the compounds of the present invention, R¹and R² are defined as described above.

Preferably R¹ and R² are ethyl or methyl, in particular methyl.

Further, in a preferred embodiment of the compounds of the presentinvention R³ is —C≡C—R⁵ with R⁵ being an organic residue; or

R³ is —R⁶C═CR⁷R⁸ with R⁶, R⁷, R⁸ being independently an organic residueand with the proviso that the C═C-bond is not part of an aromaticsystem.

In a preferred embodiment of the compounds of the present invention, R⁵is hydrogen, a trisubstituted silyl group, a substituted orunsubstituted aryl group, or a substituted or unsubstituted hetero arylgroup, or a substituted or unsubstituted alkyl group with 1 to 16 carbonatoms, or a substituted or unsubstituted cyclic alkyl group with 3 to 12carbon atoms, wherein in the substituted or unsubstituted alkyl groupwith 1 to 16 carbon atoms, the substituted or unsubstituted cyclic alkylgroup with 3 to 12 carbon atoms, optionally one or more —CH₂— group(s)can be substituted by —O—, —S—, —NR⁴—, or SiR⁴R^(4′) to form an ether, athioether, a secondary ortertiary amine, or a silylether and wherein R⁴and R^(4′) are independently hydrogen, an alkyl group with 1 to 6 carbonatoms or a cyclic alkyl group with 3 to 6 carbon atoms.

A trisubstituted silyl group is a silyl group wherein all threesubstituents are independently a substituted or unsubstituted arylgroup, a substituted or unsubstituted hetero aryl group, a substitutedor unsubstituted alkyl group with 1 to 16 carbon atoms, a substituted orunsubstituted cyclic alkyl group with 3 to 12 carbon atoms as describedabove.

A substituted or unsubstituted aryl group, a substituted orunsubstituted hetero aryl group, a substituted or unsubstituted alkylgroup with 1 to 16 carbon atoms, a substituted or unsubstituted cyclicalkyl group with 3 to 12 carbon atoms are defined as described above.

In a preferred embodiment of the compounds of the present invention, R⁵is a phenyl or a phenyl with one or more substituents. Examples ofsubstituents are alkyl groups, preferably with 1 or 2 carbon atoms,substituted alkyl groups such as trifluormethyl, alkoxy groups such asmethoxy or ethoxy, aryloxy groups such as phenoxy, amines, monoalkylsubstituted amines, monoaryl substituted amines, dialkyl substitutedamines, diaryl substituted amines, monoalkyl monoaryl substitutedamines, trisubstituted silylgroups, such as trimethylsilyl, orhalgogenides such as fluorine.

In a preferred embodiment of the compounds of the present invention, R⁵is an alkyl group with 1 to 6 carbon atoms, wherein optionally one ormore —CH₂— group(s) can be substituted by —O— or —NR⁴—, to form anether, or a secondary or tertiary amine, and wherein R⁴ is hydrogen, analkyl group with 1 or 2 carbon atoms or a cyclic alkyl group with 3carbon atoms, preferably methyl. In case of a substitution of aCH₂-group by —O—, —S— —NR⁴—, or SiR⁴R^(4′) it is preferred that thesubstitution is at the β-position to the carbon-carbon triple bond.

Examples for compounds with R³ being —C≡C—R⁵ are

In a further preferred embodiment of the compounds of the presentinvention, in Formula (I) R⁶, R⁷ and R⁸ are independently hydrogen, atrisubstituted silyl group, a substituted or unsubstituted aryl group,or a substituted or unsubstituted hetero aryl group, or a substituted orunsubstituted alkyl group with 1 to 16 carbon atoms, or a substituted orunsubstituted cyclic alkyl group with 3 to 12 carbon atoms, wherein inthe substituted or unsubstituted alkyl group with 1 to 16 carbon atoms,the substituted or unsubstituted cyclic alkyl group with 3 to 12 carbonatoms, one or more —CH₂— group(s) can be substituted by —O—, —S—, —NR⁴—,or SiR⁴R^(4′) to form an ether, a thioether, a secondary or a tertiaryamine, or a silylether and wherein R⁴ and R^(4′) are independentlyhydrogen, an alkyl group with 1 to 6 carbon atoms or a cyclic alkylgroup with 3 to 6 carbon atoms, or wherein R⁶ and R⁷ or R⁶ and R⁸together with the —C═C— double bond to which R⁶ and R⁷ or R⁶ and R⁸ areattached form a cyclic substituted or unsubstituted alkenyl group or asubstituted or unsubstituted cyclic hetero alkenyl group and theremaining R⁷ or R⁸ is defined as above.

Further, in case R³ is —R⁶C═CR⁷R⁸ the present compound refers to allpossible (Z)- and (E)-isomers thereof.

It is preferred that at least one of R⁶, R⁷ and R⁸ is hydrogen.

A trisubstituted silyl group is preferably defined as described above.

A substituted or unsubstituted aryl group, a substituted orunsubstituted hetero aryl group, a substituted or unsubstituted alkylgroup with 1 to 16 carbon atoms, a substituted or unsubstituted cyclicalkyl group with 3 to 12 carbon atoms are defined as described above.

In a preferred embodiment, one or more of R⁶, R⁷ and R⁸ is a phenyl or aphenyl with one or more substituents. Examples of substituents are alkylgroups, preferably with 1 or 2 carbon atoms, substituted alkyl groupssuch as trifluormethyl, alkoxy groups such as methoxy or ethoxy, orfluorine.

In a preferred embodiment, one or more of R⁶, R⁷ and R⁸ is an alkylgroup with 1 to 6 carbon atoms wherein optionally one or more —CH₂—group(s) can be substituted by —O—, —S—, —NR⁴— or SiR⁴R^(4′) to form anether, a thioether, a tertiary amine, or a silylether and wherein R⁴ andR^(4′) are independently an alkyl group with 1 or 2 carbon atoms or acyclic alkyl group with 3 carbon atoms. In case of a substitution of a—CH₂-group by —O—, —S—, —NR⁴—, or SiR⁴R⁴ it is preferred that thesubstitution is at the β-position to the carbon-carbon double bond.

In an alternative preferred embodiment of the invention, R⁶ and R⁷ or R⁶and R⁸ together with the —C═C— double bond to which R⁶ and R⁷ or R⁶ andR⁸ are attached form a substituted or unsubstituted cyclic alkenyl groupor a cyclic substituted or unsubstituted hetero alkenyl group. Further,the substituted or unsubstituted cyclic alkenyl group or a substitutedor unsubstituted cyclic hetero alkenyl group can comprise one or morefurther double bond(s) as long as no aromatic system is formed.

In a preferred embodiment, R⁶ and R⁷ or R⁶ and R⁸ can be selected suchthat an unsubstituted cyclic alkenyl group or an unsubstituted cyclichetero alkenyl group is formed.

Alternatively, it is preferred that R⁶ and R⁷ or R⁶ and R⁸ can beselected such that a substituted cyclic alkenyl group or a substitutedcyclic hetero alkenyl group is formed. Examples for substituents arealkyl with 1 to 4 carbon atoms, and alkoxy with 1 or 2 carbon atoms.

Examples for compounds with R³ being —R⁶C═CR⁷R⁸ are

Further, the present invention relates to the compounds according toFormula (I) for use as a medicament.

A further subject of the invention is the compound according to Formula(I) for use in the treatment of cancer, i.e. for use in an anti-tumortherapy.

An anti-tumor therapy might be understood as a therapy based on activepharmaceutical ingredients for the treatment of carcinosis. Thecompounds of the present invention are preferably cytostatic. Generally,a cytostatic drug is a compound which selectively prevents or reducesthe cell growth or inhibits the cell division of the malignant cell.Preferably, the cytostatic drug affects healthy cells as little aspossible. Generally, the cell division of malignant cells is reported tobe faster than that of healthy cells. Due to this ability the malignantcells are more sensitive to any interference of the cell growth anddivision. The present triazenes show a significant cytotoxicity, forexample to the cancer cell lines A2780 (ovarian cancer) and MDA-MB-231(invasive breast cancer).

A further subject of the present invention is a compound according toFormula (II),

R¹R^(2′)N(N₂O)M¹  Formula (II)

whereinR¹ and R² independently are an organic residue, andM¹ is a metal compound, preferably selected from Li, Na and K.

In a preferred embodiment, R¹, R² and M¹ correspond to the residues asdescribed above.

Examples of N₂O-adducts are

Further, the present invention relates to a method for preparing acompound according to Formula (II)

R^(1′)R^(2′)N(N₂O)M¹  Formula (II)

by reacting R¹R²N-M¹ with nitrous oxide, whereinR¹ and R² independently are an organic residue, andM¹ is a metal compound, preferably selected from Li, Na, and K.

Reacting R¹R²N-M¹ with nitrous oxide can be preferably carried out in asolvent, preferably in a non-protic solvent free from water or a mixtureof non-protic solvent free from water. For this purpose, a R¹R²N-M¹ canbe dissolved, preferably completely dissolved, in the solvent or themixture of solvents such as ethers such as diethyl ether ortetrahydrofuran, or alkanes such as cyclopentane, pentane or hexane.Further, the solution of a compound according to Formula (IV) ispreferably stirred under a nitrous oxide atmosphere. Alternativelypreferred, nitrous oxide can be fed into the solution of R′R²N-M¹. Thereaction of nitrous oxide with a R¹R²N-M¹ is preferably carried out attemperatures of −10° C. to 50° C., preferably of 5° C. to 40° C., morepreferably of 15° C. to 35° C., in particular of 20° C. to 27° C.Further, the completion of the reaction can preferably take 0.5 to 12hours, more preferably 1 to 9 hours, especially 2 to 6 hours.

An example of a particularly preferred reaction scheme is as follows.

The invention can be illustrated by the following examples.

EXAMPLES General Procedure for the Synthesis of Triazenes

The corresponding lithium amide (1.0 eq.) was dissolved in THF to form a0.4 M solution. The resulting solution was stirred vigorously under anatmosphere of N₂O for 4 h at 23° C. A white precipitate formed. The N₂Oatmosphere was then replaced by an atmosphere of dry N₂O. Further, undercontinuous stirring the corresponding Grignard reagent in THF (2.0 eq.)was added which resulted in the formation of a yellow solution. Afterthe completion of the addition of the Grignard reagent, the solution wasstirred for 4 h at 50° C.

Unless stated differently, the product was isolated as follows. Themixture was quenched with water (15-20 mL), extracted with ethyl acetate(3×15-20 mL) and the unified organic phases were dried over anhydrousmagnesium sulfate. A centrifuge was used to accelerate phase separation.After filtration and removal of the solvent under reduced pressure, theproduct was obtained in sufficient purity or purified as stated below.

Compound P1: 3,3-Diisopropyl-1-phenyltriaz-1-ene

The product was synthesized from lithium diisopropylamide (2.0 mmol, 214mg), N₂O and phenylmagnesium chloride in THF (1.89 M, 4.0 mmol, 2.12 mL,2.0 eq.) according to the general procedure. The crude product wasdistilled under vacuum at 80° C. using a cold finger. The product wasobtained as a pale yellow, crystalline solid (385 mg, yield: 94%).

¹H NMR (400 MHz, CDCl₃, 0° C.) δ: 7.50-7.47 (m, 2H, 2×CH_(ar)),7.40-7.35 (m, 2H, 2×CH_(ar)), 7.18-7.13 (m, 1H, CH_(ar)), 5.51-5.25 (m(br), 1H, CH), 4.14-3.87 (m (br), 1H, CH), 1.57-1.30 (m (br), 6H,2×CH₃), 1.39-1.06 (m (br), 6H, 2×CH₃);

¹³C NMR (100 MHz, CDCl₃, 0° C.) δ: 151.7 (C_(ar)), 128.9 (2×CH_(ar)),124.8 (CH_(ar)), 120.3 (2×CH_(ar)), 48.5 (br, CH), 45.5 (br, CH), 24.3(br, 2×CH₃), 19.7 (br, 2×CH₃);

HRMS (ESI-TOF): Simulated (MH+) 206.1652. found 206.1655.

Compound P2: 1-(Phenyldiazenyl)piperidine

The product was synthesized from lithium piperidinide (2.0 mmol, 182mg), N₂O and phenylmagnesium chloride in THF (1.89 M, 4.0 mmol, 2.12 mL,2.0 eq.) according to the general procedure. The crude product wasdistilled under vacuum at 80° C. using a cold finger. The product wasobtained as a pale yellow, crystalline solid (268 mg, yield: 71%).

¹H NMR (400 MHz, CDCl₃, 0° C.) δ: 7.53-7.50 (m, 2H, 2×CH_(ar)),7.43-7.38 (m, 2H, 2×CH_(ar)), 7.24-7.20 (m, 1H, CH_(ar)), 3.83-3.80 (m(br), 4H, 2×NCH₂), 1.75-1.70 (m (br), 6H, 3×CH2;

¹³C NMR (100 MHz, CDCl₃, 0° C.) δ: 150.7 (C_(ar)), 128.9 (2×CH_(ar)),125.6 (CH_(ar)), 120.4 (2×CH_(ar)), 50.2 (br, NCH₂), 46.1 (br, NCH₂),25.2 (br, 2×CH₂), 24.3 (CH₂);

HRMS (ESI-TOF): Simulated (MH+) 190.1339. found 190.1341.

Compound P3: 3,3-Diisopropyl-1-o-tolyltriaz-1-ene

The product was synthesized from lithium diisopropylamide (2.0 mmol, 214mg), N₂O and o-tolylmagnesium chloride in THF (0.94 M, 4.26 mL, 2.0 eq.)according to the general procedure. The crude product was distilledunder vacuum at 80° C. using a cold finger. The product was obtained asa pale yellow, crystalline solid (404 mg, yield: 92%).

¹H NMR (400 MHz, CDCl₃, 0° C.) δ: 7.38-7.35 (m, 1H, CH_(ar)), 7.17-7.15(m, 1H, CH_(ar)), 7.15-7.12 (m, 1H, CH_(ar)), 7.03-6.99 (m, 1H,CH_(ar)), 5.29-5.05 (m (br), 1H, CH), 4.15-3.85 (m (br), 1H, CH), 2.42(s, 3H, CH₃ (tol.)), 1.56-1.02 (m (br), 12H, 4×CH₃).

¹³C NMR (100 MHz, CDCl3, 0° C.) δ: 149.5 (C_(ar)), 132.4 (C_(ar)), 130.6(CH_(ar)), 126.2 (CH_(ar)), 124.7 (CH_(ar)), 116.3 (CHO, 49.1 (br, CH),46.2 (br, CH), 24.0 (br, 2×CH₃), 19.3 (br, 2×CH₃), 18.1 (CH₃, tol.).

HRMS (ESI-TOF): Simulated (MH+) 220.1808. found 220.1814.

Compound P4: 3,3-Diisopropyl-1-(4-methoxyphenyl)triaz-1-ene

The product was synthesized from lithium diisopropylamide (2.0 mmol, 214mg), N₂O and p-methoxymagnesium chloride in THF (0.92 M, 4.35 mL, 2.0eq.) according to the general procedure. The crude product was purifiedby flash chromatography on deactivated silica (NEt₃) with a gradient ofhexane to hexane/ethyl acetate (30%) as eluent. The product was obtainedas a yellow oil (390 mg, yield: 83%).

¹H NMR (400 MHz, CDCl3, 0° C.) δ: 7.51-7.47 (m, 2H, 2×CH_(ar)),6.98-6.94 (m, 2H, 2×CH_(ar)), 5.17-4.20 (m (br), 2H, 2×CH), 3.84 (s, 3H,OMe), 1.36 (d (br), J=6.8 Hz, 12H, 4×CH₃).

¹³C NMR (100 MHz, CDCl₃, 0° C.) δ: 157.2 (C_(ar)), 145.7 (C_(ar)), 121.1(2×CH_(ar)), 113.9 (2×CH_(ar)), 55.3 (OMe), 46.8 (2×CH), 21.7 (4×CH₃).

HRMS (ESI-TOF): Simulated (MH+) 236.1757. found 236.1761.

Compound P5: 3,3-Diisopropyl-1-(thiophen-2-yl)triaz-1-ene

The product was synthesized from lithium diisopropylamide (2.0 mmol, 214mg), N₂O and 2-thienylmagnesium chloride in THF (0.92 M, 4.35 mL, 2.0eq.) according to the general procedure. The crude product was purifiedby distillation using a cold fmger. The product was thus obtained as ayellow crystalline solid (176 mg, 42%).

¹H NMR (400 MHz, CDCl₃, 0° C.) δ: 6.90 (dd, J=5.3, 3.7 Hz, 1H, CH_(ar)),6.87 (dd, J=3.7, 1.5 Hz, 1H, CH_(ar)), 6.84 (dd, J=5.3, 1.5 Hz, 1H,CH_(ar)), 5.33-4.98 (m, 1H, CH), 4.13-3.70 (m, 1H, CH), 1.50-1.23 (m,6H, 2×CH₃), 1.35-1.07 (m, 6H, 2×CH₃).

¹³C NMR (100 MHz, CDCl₃, 0° C.) δ 159.0 (C_(ar)), 126.1 (CH_(ar)), 118.6(CH_(ar)), 116.9 (CH_(ar)), 48.8 (br, CH), 46.4 (br, CH), 24.1 (br,2×CH₃), 19.5 (br, 2×CH₃).

HRMS (ESI-TOF): Simulated (MH⁺) 212.1216. found 212.1221.

Compound P6: 1-(4-Fluorophenyl)-3,3-diisopropyltriaz-1-ene

The product was synthesized from lithium diisopropylamide (2.0 mmol, 214mg), N₂O and p-fluoromagnesium chloride in THF (0.92 M, 4.35 mL, 2.0eq.) according to the general procedure. The crude product was purifiedby flash chromatography on deactivated silica (NEt₃) with a gradient ofhexane to hexane/ethyl acetate (5%) as eluent. The product was obtainedas an yellow oil (372 mg, yield: 83%).

¹H NMR (400 MHz, CDCl₃, 0° C.) δ: 7.30-7.26 (m, 2H, 2×6.95-6.88 (m, 2H,2×5.31-5.06 (m (br), 1H, CH), 4.01-3.66 (m (br), 1H, CH), 1.40-1.12 (m(br), 6H, 2×CH₃), 1.23-1.00 (m (br), 6H, 2×CH₃).

¹³C NMR (100 MHz, CDCl₃, 0° C.) δ: 160.4 (d, J=242.4 Hz, CF), 148.1 (d,J=2.7 Hz, C_(ar)), 121.4 (d, J=7.9 Hz, 2×CH_(ar)), 115.4 (d, J=22.2 Hz,2×CH_(ar)), 48.5 (br, CH), 45.6 (br, CH), 24.1 (br, 2×CH₃), 19.5 (br,2×CH₃).

HRMS (ESI-TOF): Simulated (MH+) 224.1558. found 224.1562.

Compound P7: 1-((4-Fluorophenyl)diazenyl)pyrrolidine

The product was synthesized from lithiumpyrrolidinide (2.0 mmol, 154mg), N₂O and p-fluoromagnesium chloride in THF (0.92 M, 4.35 mL, 2.0eq.) according to the general procedure. The crude product was distilledunder vacuum at 80° C. using a cold finger. The product was obtained asa pale yellow, crystalline solid (239 mg, yield: 62%).

¹H NMR (400 MHz, CDCl₃, 0° C.) δ: 7.39-7.33 (m, 2H, 2×CH_(ar)),7.04-6.98 (m, 2H, 2×CH_(ar)), 4.01-3.71 (m (br), 2H, NCH₂), 3.83-3.55 (m(br), 2H, NCH₂), 2.10-1.93 (m (br), 4H, 2×CH₂).

¹³C NMR (100 MHz, CDCl₃, 0° C.) δ: 160.6 (d, J=243.0 Hz, CF), 147.8 (d,J 2.8 Hz, C_(ar)), 121.5 (d, J=8.0 Hz, CH_(ar)), 115.6 (d, J=22.3 Hz,CH_(ar)), 51.1 (br, NCH₂), 46.4, NCH₂), 23.9 (br, 2×CH₂).

HRMS (ESI-TOF): Simulated (MH+) 194.1088. found 194.1093.

Compound 1: 3,3-Diisopropyl-1-(phenylethynyl)triaz-1-ene

The product was synthesized from lithium diisopropylamide (3.0 mmol, 321mg), N₂O and phenethynylmagnesium bromide in THF (0.71 M, 8.49 mL, 2.0eq.) according to the general procedure. After filtration and removal ofthe solvent under reduced pressure, the crude product was purified byfractionated recrystallization from pentane at −20° C. The product wasobtained as a white crystalline solid (447 mg, yield: 65%).

¹H NMR (400 MHz, CDCl₃) δ: 7.46-7.44 (m, 2H, 2×CH_(ar)), 7.31-7.20 (m,3H, 3×CH_(ar)), 5.12 (sept, J=6.8 Hz, 1H, CH), 4.05 (sept, J=6.8 Hz, 1H,CH), 1.38 (d, J=6.8 Hz, 6H, 2×CH₃), 1.24 (d, J=6.8 Hz, 6H, 2×CH₃).

¹³C NMR (100 MHz, CDCl₃): 131.2 (2×CH_(ar)), 128.3 (2×CH_(ar)) 127.1(CH_(ar)), 124.9 (C_(ar)), 94.0 (C_(sp)), 80.2 (C_(sp)), 50.5 (CH), 47.5(CH), 23.5 (2×CH₃), 19.2 (2×CH₃).

HRMS (ESI-TOF): Simulated (MH+) 230.1657. found 230.1655.

Compound 2: 1-(3,3-Dimethylbut-1-ynyl)-3,3-diisopropyltriaz-1-ene

The product was synthesized from lithium diisopropylamide (3.0 mmol, 321mg), N₂O and tert-butylethynylmagnesium bromide in THF (0.70 M, 8.57 mL,2.0 eq.) according to the general procedure. The product was obtained asa white, crystalline solid (521 mg, yield: 83%).

¹H NMR (400 MHz, CDCl₃) δ: 5.08-4.97 (m (br), 1H, CH), 4.02-3.93 (m(br), 1H, CH), 1.32 (d (br), J=6.0 Hz, 6H, 2×CH₃), 1.31 (s, 9H, tBu),1.18 (d (br), J=6.0 Hz, 6H, 2×CH₃).

¹³C NMR (100 MHz, CDCl₃) δ: 88.5 (C_(sp)), 84.2 (C_(sp)), 49.9 (br, CH),46.7 (br, CH), 31.7 (3×CH₃, tBu), 28.2 (C_(sp) ³), 23.5 (br, 2×CH₃),19.3 (br, 2×CH₃).

HRMS (ESI-TOF): Simulated (MH+) 210.1970. found 210.1976.

Compound 3: 1-((3,3-Dimethylbut-1-ynyl)diazenyl)piperidine

The product was synthesized from lithium piperidinide (2.0 mmol, 182mg), N₂O and tert-butylethynylmagnesium bromide in THF (0.70 M, 5.71 mL,4.0 mmol, 2.0 eq.) according to the general procedure. The product wasobtained as a brown solid (251 mg, yield: 65%).

¹H NMR (400 MHz, CDCl₃) δ: 3.73-3.67 (m (br), 4H, 2×NCH₂), 1.74-1.63 (m(br), 4H, 2×CH₂), 1.63-1.53 (m (br), 2H, CH₂) 1.27 (s, 9H, tBu).

¹³C NMR (100 MHz, CDCl₃) δ: 90.1 (C_(sp)), 83.2 (C_(sp)), 53.2 (NCH₂),43.5 (NCH₂), 31.4 (3×CH₃, tBu), 28.1 (C_(sp) ³), 26.2 (CH₂), 24.3 (CH₂),24.0 (CH₂).

HRMS (ESI-TOF): Simulated (MH+) 194.1657. found 194.1654.

Compound 4: 1-(3,3-Dimethylbut-1-ynyl)-3-isopropyl-3-methyltriaz-1-ene

The product was synthesized from lithium isopropyl(methyl)amide (2.0mmol, 158 mg), N₂O and tert-butylethynylmagnesium bromide in THF (0.70M, 5.71 mL, 4.0 mmol, 2.0 eq.) according to the general procedure. Theproduct was obtained as a pale yellow crystalline solid (265 mg, yield:73%).

¹H NMR (400 MHz, CDCl₃) δ: 4.21 (hept, J=6.7 Hz, 1H, CH), 2.96 (s, 3H,NMe), 1.26 (s, 9H, tBu), 1.25 (d, J=6.7 Hz, 6H, 2×CH₃).

¹³C NMR (100 MHz, CDCl₃) δ: 88.0 (C_(sp)), 83.8 (C_(sp)), 57.1 (CH),31.5 (3×CH₃, tBu), 30.8 (NMe), 28.1 (C_(sp) ³), 20.7 (2×CH₃).

HRMS (ESI-TOF): Simulated (MH+) 182.1657. found 182.1656.

Compound 5: 1-(3,3-Dimethylbut-1-ynyl)-3,3-dimethyltriaz-1-ene

The product was synthesized from lithium dimethylamide (2.0 mmol, 102mg), N₂O and tert-butylethynylmagnesium bromide in THF (0.70 M, 5.71 mL,4.0 mmol, 2.0 eq.) according to the general procedure. The product wasobtained as a pale yellow crystalline solid (93 mg, yield: 30%).

¹H NMR (400 MHz, CDCl₃) δ: 3.41 (s (br), 3H, NMe), 3.04 (s (br), 3H,NMe), 1.23 (s, 9H, tBu).

¹³C NMR (100 MHz, CDCl₃) δ: 88.5 (C_(sp)), 83.5 (C_(sp)), 43.3 (NMe),36.1 (NMe), 31.4 (3×CH₃, tBu), 28.0 (C_(sp) ³)

HRMS (APPI-Orbitrap): Simulated (MH+) 154.1339. found 154.1341.

Compound 6: 1-(Hex-1-ynyl)-3,3-diisopropyltriaz-1-ene

The product was synthesized from lithium diisopropylamide (3.0 mmol, 321mg), N₂O and n-hexynylmagnesium bromide in THF (0.54 M, 6.0 mmol, 11.11mL, 2.0 eq.) according to the general procedure. The product wasobtained as a yellow oil (581 mg, yield: 93%).

¹H NMR (400 MHz, CDCl₃) δ: 4.92-4.77 (m (br), 1H, CH), 3.94-3.72 (m(br), 1H, CH), 2.30 (t, J=7.2 Hz, 2H, NCH₂), 1.44-1.35 (m, 2H, CH₂),1.35-1.25 (m, 2H, CH₂), 1.16 (d (br), J=5.6 Hz, 6H, 2×CH₃), 1.03 (d,J=6.0 Hz, 6H, 2×CH₃), 0.77 (t, J=7.2 Hz, 3H, CH₃).

¹³C NMR (100 MHz, CDCl₃) δ: 85.0 (C_(sp)), 79.4 (C_(sp)), 49.4 (br, CH),46.3 (br, CH), 31.2 (CH₂), 23.1 (2×CH₃, iPr), 21.8 (CH₂), 19.0 (CH₂)18.7 (2×CH₃, iPr), 13.4 (CH₃, nBu).

HRMS (ESITOF): Simulated (MH+) 210.1970. found 210.1980.

Compound 7: 3,3-Diisopropyl-1-(3-methoxyprop-1-ynyl)triaz-1-ene

The product was synthesized from lithium diisopropylamide (2.0 mmol, 214mg), N₂O and (3-methoxyprop-1-yn-1-yl)magnesium bromide in THF (0.64 M,6.22 mL, 4.0 mmol, 2.0 eq.) according to the general procedure. Theproduct was obtained as a brown oil (331 mg, yield: 84%).

¹H NMR (400 MHz, CDCl₃) δ: 5.04 (hept, J=6.8 Hz, 1H, CH), 4.40 (s, 2H,CH₂), 4.01 (hept, J=6.8 Hz, 1H), 3.42 (s, 3H, OMe), 1.32 (d, 6H, J=6.8Hz, 2×CH₃), 1.20 (d, J=6.8 Hz, 6H, 2×CH₃).

¹³C NMR (100 MHz, CDCl₃) δ: 90.7 (C_(sp)), 74.5 (C_(sp)), 61.0 (OMe),57.5 (OCH₂), 50.4 (CH), 47.4 (CH), 23.5 (2×CH₃), 19.1 (2×CH₃).

HRMS (ESI-TOF): Simulated (MH+) 198.1606. found 198.1609.

Compound 8:3-(3,3-Diisopropyltriaz-1-enyl)-N,N-dimethylprop-2-yn-1-amine

The product was synthesized from lithium diisopropylamide (2.0 mmol, 214mg), N₂O and (3-(dimethylamino)prop-1-yn-1-yl)magnesium bromide in THF(0.63 M, 6.31 mL, 4.0 mmol, 2.0 eq.) according to the general procedure.The product was obtained as a brown oil (366 mg, yield: 87%).

¹H NMR (400 MHz, CDCl₃) δ: 4.98 (hept, J=6.6 Hz, 1H, CH), 3.93 (hept,J=6.6 Hz, 1H, CH), 3.49 (s, 2H, CH₂), 2.28 (s, 6H, NMe₂), 1.27 (d, J=6.6Hz, 6H, 2×CH₃), 1.14 (d, J=6.6 Hz, 6H, 2×CH₃).

¹³C NMR (100 MHz, CDCl₃) δ: 89.7 (C_(sp)), 73.7 (C_(sp)), 49.9 (CH),48.9 (CH₂), 46.9 (CH), 44.2 (NMe), 23.4 (2×CH₃), 19.1 (2×CH₃).

HRMS (ESI-TOF): Simulated (MH+) 211.1923. found 211.1921.

Compound 9: 3-Isopropyl-1-(3-methoxyprop-1-ynyl)-3-methyltriaz-1-ene

The product was synthesized from lithium isopropyl(methyl)amide (2.0mmol, 158 mg), (2.0 mmol, 214 mg), N₂O and(3-methoxyprop-1-yn-1-yl)magnesium bromide in THF (0.64 M, 6.22 mL, 4.0mmol, 2.0 eq.) according to the general procedure. The crude product waspurified by flash chromatography on deactivated silica (NEt₃) with agradient of hexane/ethyl acetate (5%) to hexane/ethyl acetate (20%) aseluent. The product was obtained as a colorless oil (169 mg, yield:50%).

¹H NMR (400 MHz, CDCl₃) δ: 4.38 (s, 2H, CH₂), 4.20 (hept, J=6.8 Hz, 1H,CH), 3.41 (s, 3H, OMe), 3.04 (s, 3H, NMe), 1.30 (d, J=6.8 Hz, 6H,2×CH₃).

¹³C NMR (100 MHz, CDCl₃) δ: 90.3 (C_(sp)), 73.9 (C_(sp)), 60.8 (OMe),57.7 (CH), 57.4 (CH₂), 31.8 (NMe), 20.8 (2×CH₃).

HRMS (ESI-TOF): Simulated (MH+) 170.1288. found 170.1287.

Compound 10:3-(3-Isopropyl-3-methyltriaz-1-enyl)-N,N-dimethylprop-2-yn-1-amine

The product was synthesized from lithium isopropyl(methyl)amide (2.0mmol, 158 mg), N₂O and (3-(dimethylamino)prop-1-yn-1-yl) magnesiumbromide in THF (0.63 M, 6.31 mL, 4.0 mmol, 2.0 eq.) according to thegeneral procedure. The crude product was purified by flashchromatography on deactivated silica (NEt3) with ethyl acetate aseluent. The product was obtained as a yellow oil (190 mg, yield: 52%).

¹H NMR (400 MHz, CDCl₃) δ: 4.19 (hept, J=6.8 Hz, 1H, CH), 3.53 (s, 2H,CH₂), 3.01 (s, 3H, NMe), 2.31 (s, 6H, NMe₂), 1.29 (d, J=6.8 Hz, 6H,2×CH₃).

¹³C NMR (100 MHz, CDCl₃) δ: 89.4 (C_(sp)), 73.3 (C_(sp)), 57.5 (CH),48.8 (CH₂), 44.2 (NMe₂), 31.5 (NMe), 20.8 (2×CH₃).

HRMS (ESI-TOF): Simulated (MH+) 183.1604. found 183.1603.

Compound 11: 3-Cyclohexyl-1-(hex-1-ynyl)-3-methyltriaz-1-ene

The product was synthesized from lithium cylclohexylmethylamide (2.0mmol, 214 mg), N₂O and n-hexynylmagnesium bromide in THF (0.54 M, 4.0mmol 7.41 mL, 2.0 eq.)) according to the general procedure. Afterfiltration and removal of the solvent under reduced pressure, the crudeproduct was purified by flash chromatography with on deactivated silica(NEt₃) with hexane/ethyl acetate (5%) as eluent. The product wasobtained as a colorless oil (249 mg, 56%).

¹H NMR (400 MHz, CDCl₃) δ 3.74 (tt, J=12.1, 3.6 Hz, 1H, CH), 3.02 (s,3H, NMe), 2.44 (t, J=7.0 Hz, 2H, CH₂), 1.90-1.81 (m, 4H, 2×CH₂),1.70-1.64 (m, 1H, CHH), 1.59-1.51 (m, 4H, 2×CH₂), 1.48-1.40 (m, 2H,CH₂), 1.37-1.26 (m, 2H, CH₂), 1.19-1.11 (m, 1H, CHH), 0.90 (t, J=7.3 Hz,3H, CH₃).

¹³C NMR (100 MHz, CDCl₃) δ: 85.1 (C_(sp)), 79.5 (C_(sp)), 65.3 (CH),32.3 (NCH₃), 31.5 (CH₂), 31.3 (2×CH₂), 25.6 (2×CH₂), 25.4 (CH₂), 22.2(CH₂), 19.2 (CH₂), 13.8 (CH₃).

HRMS (ESI-TOF): Simulated (MH⁺) 222.1970. found 222.1973.

Compound 12: 1-(3,3-Dimethylbut-1-ynyl)-3,3-diethyltriaz-1-ene

The product was synthesized from lithium diethylamide (2.0 mmol, 163mg), N₂O and tert-butylethynylmagnesium bromide in THF (0.70 M, 5.71 mL,4.0 mmol, 2.0 eq.) according to the general procedure. The product wasobtained as an orange oil (163 mg, yield: 45%).

¹H NMR (400 MHz, CDCl₃, 0° C.) δ: 3.68 (q, J=7.2 Hz, 1H), 3.58 (q, J=7.1Hz, 1H), 1.23 (s, 4H), 1.21 (t, J=7.3 Hz, 2H), 1.08 (t, J=7.1 Hz, 2H).

¹³C NMR (100 MHz, CDCl₃, 0° C.) δ: 88.3 (C_(sp)), 83.8 (C_(sp)), 49.5(br, CH₂), 41.5 (br, CH₂), 31.6 (3×CH₃, tBu), 28.1 (C_(sp) ³), 14.4 (br,CH₃), 11.1 (br, CH₃).

HRMS (ESI-TOF): Simulated (MH+) 182.1657. found 182.1655.

Compound 13: 3,3-Dimethyl-1-(phenylethynyl)triaz-1ene

The product was synthesized from lithium dimethylamide (2.0 mmol, 214mg), N₂O and phenethynylmagnesium bromide in THF (0.71 M, 8.49 mL, 4.0mmol, 2.0 eq.) according to the general procedure. The product wasobtained as a brown solid (163 mg, yield: 47%).

¹H NMR (400 MHz, CDCl₃) δ: 7.39-7.34 (m, 2H, 2×CH_(ar)), 7.28-7.15 (m,3H, 3×CH_(ar)), 3.47 (s, 3H, CH₃), 3.13 (s, 3H, CH₃).

¹³C NMR (100 MHz, CDCl₃) δ: 131.2 (2×CH_(ar)), 128.2 (2×CH_(ar)) 127.2(CH_(ar)), 124.3 (C_(ar)), 93.0 (C_(sp)), 80.1 (C_(sp)), 43.7 (CH₃),36.6 (CH₃).

HRMS (APPI-Orbitrap): Simulated (MH+) 173.0948. found 173.0945.

Compound 14: 1-(3-Methoxyprop-1-ynyl)-3,3-dimethyltriaz-1-ene

The product was synthesized from lithium diisopropylamide (2.0 mmol, 214mg), N₂O and (3-methoxyprop-1-yn-1-yl)magnesium bromide in THF (0.64 M,6.22 mL, 4.0 mmol, 2.0 eq.) according to the general procedure. Theproduct was obtained as an yellow oil (51 mg, yield: 18%).

¹H NMR (400 MHz, CDCl₃) δ: 4.34 (s, 2H, CH₂), 3.47 (3.41 (s, 3H, NMe),3.37 (s, 3H, OMe), 3.11 (s, 3H, NMe).

¹³C NMR (100 MHz, CDCl₃) δ: 89.8 (C_(sp)), 74.3 (C_(sp)), 60.6 (OMe),57.3 (CH₂), 43.6 (NMe), 36.4 (NMe).

HRMS (ESI-TOF): Simulated (MH+) 142.0980. found 142.0986.

Compound 15: 3-(3,3-Dimethyltriaz-1-enyl)-N,N-dimethylprop-2-yn-1-amine

The product was synthesized from lithium diisopropylamide (2.0 mmol, 214mg), N₂O and (3-(dimethylamino)prop-1-yn-1-yl)magnesium bromide in THF(0.63 M, 6.31 mL, 4.0 mmol, 2.0 eq.) according to the general procedure.The product was obtained as a yellow oil (99 mg, yield: 32%).

¹H NMR (400 MHz, CDCl₃) δ: 3.55 (s, 2H, CH₂), 3.48 (s, 3H, (N═NNMe)CH₃),3.13 (s, 3H, (N═N—NMe)CH₃), 2.32 (s, 6H (CH₂N)Me₂).

¹³C NMR (100 MHz, CDCl₃) δ: 89.0 (C_(sp)), 73.6 (C_(sp)), 48.6 (CH₂),44.0 ((CH₂N)Me₂), 43.4 ((N═N—NMe)CH₃), 36.2 ((N═N—NMe)CH₃).

HRMS (ESI-TOF): Simulated (MH+) 155.1297. found 155.1294.

Compound 16: 3, 3-Diisopropyl-1-(2-methylprop-1-enyl)triaz-1-ene

The product was synthesized from lithium diisopropylamide (3.0 mmol, 321mg), N₂O and 2-methyl-1-propenylmagnesium bromide in THF (0.54 M, 6.0mmol, 11.11 mL, 2.0 eq.) according to the general procedure. The crudeproduct was purified by flash chromatography on deactivated silica(NEt₃) with a gradient of hexane to hexane/ethyl acetate (5%) as eluent.The product was obtained as a colorless oil (484 mg, yield: 88%).

¹H NMR (400 MHz, CDCl₃) δ: 6.78 (qq, J=1.2 Hz, J=1.2 Hz, 1H, CH_(olef)),4.73-4.15 (m (br), 2H, 2×CH), 1.99 (m, 3H, CH₃, dimethylvinyl),1.81-1.80 (m, 3H, CH₃, dimethylvinyl), 1.25 (d, J=6.8 Hz, 6H, 2×CH₃,iPr).

¹³C NMR (100 MHz, CDCl₃) δ: 138.0 (CH_(olef)), 125.9 (C_(olef)), 47.1(br, 2×CH), 22.8 (CH₃, dimethylvinyl), 21.5 (br, 4×CH₃, iPr), 17.5 (CH₃,dimethylvinyl).

HRMS (ESI-TOF): Simulated (MH+) 184.1814. found 184.1808.

Compound 17: 1-Cyclohexenyl-3,3-diisopropyltriaz-1-ene

The product was synthesized from lithium diisopropylamide (2.0 mmol, 214mg), N₂O and 1-cyclohexenylmagnesium bromide in THF (0.33 M, 4.0 mmol,12.12 mL, 2.0 eq.) according to the general procedure. The crude productwas purified by flash chromatography on deactivated silica (NEt₃) with agradient of hexane to hexane/ethyl acetate (5%) as eluent. The productwas obtained as a colorless oil (310 mg, yield: 74%).

¹H NMR (400 MHz, CDCl₃) δ: 5.84 (tt, J=4.2, 1.4 Hz, 1H, CH_(olef)),4.70-4.32 (m, 2H, 2×CH), 2.36-2.32 (m, 2H, CH₂), 2.25-2.21 (m, 2H, CH₂),1.75-1.69 (m, 2H, CH₂), 1.65-1.60 (m, 2H, CH₂), 1.21 (d, J=6.7 Hz, 12H,4×CH₃).

¹³C NMR (100 MHz, CDCl₃) δ: 149.8 (C_(olef)), 120.0 (CH_(olef)), 46.2(br, CH), 25.3 (CH₂), 24.3 (CH₂), 23.1 (CH₂), 23.0 (CH₂), 21.7 (br,4×CH₃).

HRMS (ESI-TOF): Simulated (MH+) 210.1970. found 210.1971.

Compound 18: 1-Cyclohexenyl-3-isopropyl-3-methyltriaz-1-ene

The product was synthesized from lithium isopropyl(methyl)amide (2.0mmol, 158 mg), N₂O and 1-cyclohexenylmagnesium bromide in THF (0.33 M,4.0 mmol, 12.12 mL, 2.0 eq.) according to the general procedure. Thecrude product was purified by flash chromatography on deactivated silica(NEt₃) with a gradient of hexane to hexane/ethyl acetate (5%) as eluent.The product was obtained as a colorless oil (265 mg, yield: 73%).

¹H NMR (400 MHz, CDCl₃) δ: 5.91 (tt, J=4.2, 1.3 Hz, 1H, CH_(olef)), 4.06(hept, J=6.6 Hz, 1H, CH), 2.95 (s, 3H, NMe), 2.33-2.29 (m, 2H, CH₂),2.24-2.20 (m, 2H, CH₂), 1.74-1.68 (m, 2H, CH₂), 1.64-1.59 (m, 2H, CH₂),1.24 (d, J=6.7 Hz, 6H).

¹³C NMR (100 MHz, CDCl₃) δ: 149.4 (C_(olef)), 121.2 (CH_(olef)), 55.5(CH), 31.1 (NMe), 25.3 (CH₂), 24.3 (CH₂), 23.0 (CH₂), 22.9 (CH₂), 20.8(2×CH₃).

HRMS (ESI-TOF): Simulated (MH+) 182.1657. found 182.1654.

Compound 19: 3-Isopropyl-3-methyl-1-(2-methylprop-1-enyl)triaz-1-ene

The product was synthesized from lithium isopropyl(methyl)amide (2.0mmol, 158 mg), N₂O and 2-methyl-1-propenylmagnesium bromide in THF (0.54M, 4.0 mmol, 7.41 mL, 2.0 eq.) according to the general procedure. Thecrude product was purified by flash chromatography on deactivated silica(NEt₃) with a gradient of pentane to pentane/diethyl ether (5%) aseluent. The product was thus obtained as a colorless (volatile) oil (58mg, yield: 19%).

¹H NMR (400 MHz, CDCl₃) δ: 6.77-6.76 (m, 1H, CH_(olef)), 4.11 (hept,J=6.5 Hz, 1H, CH), 2.94 (s, 2H, NMe), 1.98 (s, 3H, CH₃, dimethylvinyl),1.79 (s, 3H, CH₃, dimethylvinyl), 1.24 (d, J=6.8 Hz, 4H, 2×CH₃, iPr).

¹³C NMR (100 MHz, CDCl₃) δ: 137.4 (CH_(olef)), 127.8 (C_(olef)), 55.1(br, CH), 30.9 (NMe), 22.9 (CH₃, dimethylvinyl), 22.7 (br, 2×CH₃, iPr),17.6 (CH₃, dimethylvinyl).

HRMS (ESI-TOF): Simulated (MH+) 156.1501. found 156.1503.

Compound 20: 3,3-Dicyclohexyl-1-vinyltriaz-1-ene

The product was synthesized from lithium dicyclohexylamide (2.0 mmol,374 mg), N₂O and vinylmagnesium bromide in THF (1.80 M, 8.49 mL, 2.0eq.) according to the general procedure. After filtration and removal ofthe solvent under reduced pressure, the crude product was purified byflash chromatography with on deactivated silica (NEt₃) with a gradientof hexane to hexane/ethyl acetate (5%) as eluent. The product wasobtained as a white solid (423 mg, 90%).

¹H NMR (400 MHz, CDCl₃, 0° C.) δ 7.16 (dd, J=15.5, 7.8 Hz, 1H,CH_(olef)), 5.17 (d, J=15.5 Hz, 1H, CH_(olef)), 5.00-4.82 (m, 1H, CH),4.76 (d, J=8.1 Hz, 1H, CH_(olef)), 3.53-3.22 (m, 1H, CH), 1.84-1.64 (m,12H, 6×CH₂), 1.49-1.25 (s, 6H, 3×CH₂), 1.19-1.07 (d, 2H, 1×CH₂).

¹³C NMR (100 MHz, CDCl₃) δ 149.2 (CH_(olef)), 104.5 (CH_(2,olef)), 56.9(br, CH), 53.5 (br, CH), 34.1 (br, 2×CH₂), 29.9 (br, 2×CH₂), 26.2 (br,2×CH₂), 25.7 (br, 3×CH₂), 25.4 (CH₂).

HRMS (ESI-TOF): Simulated (MH⁺) 236.2127. found 237.2157.

Compound 21: 1-(1,2-Diphenylvinyl)-3,3-diisopropyltriaz-1-ene

The product was synthesized from lithium diisopropylamide (2.0 mmol, 214mg) and (E)-(1,2-diphenylvinyl)magnesium bromide in THF (0.66 M, 6.00mL, 4.0 mmol) according to the general procedure. The crude product waspurified by flash chromatography with a gradient of hexane tohexane/ethyl acetate (10%). The product was obtained as a mixture of theE and Z isomer as a yellow oil (440 mg, 72%).

An attribution of the spectra to the respective isomers was attempted by1D-NOESY and HMBC experiments, indicating that Isomer 1 (39%) is the Eisomer and Isomer 2 (61%) is the Z isomer.

Isomer 1:

¹H NMR (400 MHz, CDCl₃, 0° C.) δ: 7.81 (d, J=7.3 Hz, 2H, CH_(ar)),7.37-6.97 (m, 9H, 9×CH_(ar)), 6.17 (s, 1H, CH_(olef)), 5.39 (hept, J=6.8Hz, 1H, CH), 3.86 (hept, J=6.6 Hz, 1H, CH), 1.25 (d, J=6.8 Hz, 6H), 1.10(d, J=6.6 Hz, 6H).

¹³C NMR (100 MHz, CDCl₃) δ: 151.1 (C_(olef/ar)), 140.6 (C_(olef/ar)),137.6 (C_(olef/ar)), 130.0 (2×CH_(ar)), 129.2 (2×CH_(ar)), 128.0(2×CH_(ar)), 127.3 (2×CH_(ar)), 126.9 (CH_(ar)), 125.9 (CH_(ar)), 119.4(CH_(olef)), 48.5 (CH), 45.8 (CH), 23.8 (2×CH₃), 19.5 (2×CH₃).

Isomer 2:

¹H NMR (400 MHz, CDCl₃) δ: 7.37-6.97 (m, 10H, 10×CH_(ar)), 6.77 (s, 1H,CH_(olef)), 5.39-5.16 (m (br), 1H, CH), 3.88-3.66 (m (br), 1H, CH),1.23-1.09 (m (br), 6H, 2×CH₃), 1.09-0.93 (m (br), 6H, 2×CH₃).

¹³C NMR (100 MHz, CDCl₃) δ: 152.7 (C_(olef/ar)), 137.9 (C_(olef/ar)),137.2 (C_(olef/ar)), 130.0 (2×CH_(ar)), 129.0 (2×CH_(ar)), 128.0(2×CH_(ar)), 127.9 (2×CH_(ar)), 127.1 (CH_(ar)), 125.8 (CH_(ar)), 121.8(CH_(olef)), 48.2 (CH), 45.1 (CH), 23.6 (2×CH₃), 19.5 (2×CH₃).

HRMS (mixture of isomers, ESI-TOF): Simulated (MH⁺) 308.2127. found308.2119.

Compound 22: 3,3-Diisopropyl-1-styryltriaz-1-ene

The product was synthesized from lithium diisopropylamide (2.0 mmol, 214mg), N₂O and β-stryrylmagnesium bromide (E/Z of the bromide=89:11) inTHF (0.71 M, 8.49 mL, 2.0 eq.) according to the general procedure. Afterfiltration and removal of the solvent under reduced pressure, the crudeproduct was purified by flash chromatography with on deactivated silica(NEt₃) with a gradient of hexane to hexane/ethyl acetate (5%) as eluent.The minor E isomer was obtained as a pale yellow solid (13 mg). The Zisomer was obtained as a pale yellow oil (203 mg). The total isolatedyield of both isomers (E/Z=94:6) was 216 mg (47%).

E-isomer:

¹H NMR (400 MHz, CDCl₃, 0° C.) δ 7.61 (d, J=14.1 Hz, 1H, CH_(olef)),7.28-7.26 (m, 2H, 2×CH_(ar)), 7.15-7.11 (m, 2H, 2×CH_(ar)), 7.02-6.98(m, 1H, CH_(ar)), 6.50 (d, J=14.1 Hz, 1H, CH_(olef)), 5.15-5.00 (m (br),1H, CH), 3.84-3.65 (m (br), 1H, CH), 1.26-1.04 (m (br), 6H, 2×CH₃),1.15-0.88 (m (br), 6H, 2×CH₃).

¹³C NMR (100 MHz, CDCl₃) δ 143.2 (CH_(olef)), 137.5 (C_(ar)), 128.6(2×CH_(ar)), 126.4 (CH_(ar)), 126.0 (2×CH_(ar)), 121.8 (CH_(olef)), 48.3(CH), 45.8 (CH), 23.7 (2×CH₃), 19.6 (2×CH₃).

Z-isomer:

¹H NMR (400 MHz, CDCl₃) δ 7.79-7.77 (m, 2H, 2×CH_(ar)), 7.26-7.23 (m,2H, 2×CH_(ar)), 7.12-7.07 (m, 1H, CH_(ar)), 7.06 (d, J=9.0 Hz, 1H,CH_(olef)), 5.79 (d, J=9.0 Hz, 1H, CH_(olef)), 5.13 (sept, J=6.8 Hz, 1H,CH), 3.91 (sept, J=6.8 Hz, 1H, CH), 1.26 (d, J=6.8 Hz, 6H, 2×CH₃), 1.19(d, J=6.8 Hz, 6H, 2×CH₃).

¹³C NMR (100 MHz, CDCl₃) δ 142.0 (CH_(olef)), 137.5 (C_(ar)), 129.6(2×CH_(ar)), 128.2 (2×CH_(ar)), 126.0 (2×CH_(ar)), 117.0 (CH_(olef)),48.8 (CH), 47.0 (CH), 23.7 (2×CH₃), 19.3 (2×CH₃).

HRMS (mixture of isomers, ESI-TOF): Simulated (MH⁺) 232.1814. found232.1805.

Compound 23: 3,3-Diisopropyl-1-((Z)-4-methoxystyryl)triaz-1-ene

The product was synthesized from lithium diisopropylamide (2.0 mmol, 214mg), N₂O and (Z)-(4-methoxystyryl)magnesium bromide in THF (0.60 M, 6.66mL, 4.0 mmol) according to the general procedure. The crude product wasdissolved in a minimal amount of dichloromethane, hexane was slowlyadded until the solution became slightly turbid and the mixture wasplaced in a fridge overnight (4° C.).

The product crystallized and the supernatant solution was discarded. Thecrystals were powdered, washed with cold pentane (−20° C.) and driedunder vacuo (298 mg, 57%).

¹H NMR (400 MHz, CDCl₃, 0° C.) δ 7.82 (d, J=8.8 Hz, 2H, 2×CH_(ar)), 7.06(d, J=9.0 Hz, 1H, CH_(olef)), 6.88 (d, J=8.8 Hz, 2H, 2×CH_(ar)), 5.83(d, J=9.0 Hz, 1H, CH_(olef)), 5.19 (hept, J=6.7 Hz, 1H, CH), 3.96 (hept,J=6.5 Hz, 1H, CH), 3.82 (s, 3H, OMe), 1.34 (d, J=6.6 Hz, 5H, 2×CH₃),1.28 (s, 3H, 2×CH₃).

¹³C NMR (100 MHz, CDCl₃, 0° C.) 5 ¹³C NMR (100 MHz, CDCl₃) δ 157.8(C_(ar)), 140.1 (CH_(olef)), 130.9 (2×CH_(ar)), 130.4 (C_(ar)), 116.7(CH_(olef)), 113.5 (2×CH_(ar)), 55.3 (OMe), 48.6 (CH), 46.8 (CH), 23.7(2×CH₃), 19.3 (2×CH₃).

HRMS (ESI-TOF): Simulated (MH⁺) 262.1919. Found 262.1914.

Synthesis of the N₂O Adducts

Lithium diethylamide (10.0 mmol, 791 mg) was dissolved in THF (10 mL).The solution was stirred for 4 h under a N₂O atmosphere and a whiteprecipitate appeared. The precipitate was isolated by filtration, washedwith THF (20 mL) and pentane (3×40 mL), and dried under vacuum. Yield:1083 mg, 88%.

¹H NMR ([D₆]DMSO) δ: 2.55 (q, J=7.2 Hz, 4H, CH₂), 0.87 (t, J=7.2 Hz, 6H,CH₃).

¹³C NMR ([D₆]DMSO) δ: 48.2 (CH₂), 11.9 (CH₃).

Elemental Analysis (C₄H₁₀LiN₃O): Required C, 39.03 H, 8.19 N, 34.14.Found C, 38.92 H, 8.10, N, 34.12.

Lithium diisopropylamide (0.47 mmol, 50 mg) was dissolved in THF (1 mL).The solution was stirred for 4 h under an N₂O atmosphere and a whiteprecipitate appeared. The precipitate was isolated by centrifugation,washed with THF (3 mL) and pentane (3×10 mL), and dried under vacuum.Yield: 67 mg, 95%.

¹H NMR ([D₆]DMSO) δ: 2.33 (sept, 6.4 Hz, 2H, CH), 0.47 (d, J=6.4 Hz,12H, CH₃).

¹³C NMR ([D₆]DMSO) δ: 49.2 (CH), 18.8 (CH₃).

Elemental Analysis (C₆H₁₅LiN₃O): Required C, 47.68 H, 9.34 N, 27.80.Found C, 47.50 H, 9.48, N, 27.68.

Lithium pyrrolidinide (10.0 mmol, 771 mg) was dissolved in THF (5 mL).The solution was stirred for 4 h under an N₂O atmosphere and a whiteprecipitate appeared. The precipitate was isolated by filtration, washedwith THF (20 mL) and pentane (3×40 mL), and dried under vacuum. Thedried product still contained traces of THF (˜8 mol %). Yield: 866 mg,68%.

¹H NMR ([D₆]DMSO) δ: 2.76-2.73 (m, 4H, NCH₂), 1.65-1.62 (m, 4H, CH₂).

¹³C NMR ([D₆]DMSO) δ: 52.0 (NCH₂), 22.6 (CH₂).

Elemental Analysis (C₄H₈LiN₃O×0.08 THF): Required C, 40.91, H, 6.87, N,33.13. Found C, 40.74 H, 7.01, N, 33.13

Lithium piperidinide (10.0 mmol, 911 mg) was dissolved in THF (10 mL).The solution was stirred for 4 h under an N₂O atmosphere and a whiteprecipitate appeared. The precipitate was isolated by filtration, washedwith THF (20 mL) and pentane (3×40 mL), and dried under vacuum. Thedried product still contained traces of THF (˜4 mol %). Yield: 1000 mg,72%.

¹H NMR ([D₆]DMSO) δ: 2.64-2.40 (m (br), 4H, NCH₂), 1.55-1.53 (m, 4H,CH₂), 1.35-1.34 (m, 2H, CH₂).

¹³C NMR ([D₆]DMSO) δ: 52.4 (NCH₂), 24.4 (NCH₂CH₂), 23.8 (NCH₂CH₂CH₂).

Elemental Analysis (C₅H₁₀LiN₃O×0.04 THF): Required C, 44.92, H, 7.54, N,30.45. Found C, 44.44, H, 7.31, N, 30.21.

Cytotoxicity Tests:

MDA-MB-231 breast adenocarcinoma cells (ATCC® HTB-26™), MCF-10a humanmammary epithelial cells (ATCC® CRL-10317™) and HEK293 human embryonickidney cells (ATCC® CRL-1573™) were obtained from ATCC (Middlesex, UK),the A2780 human ovarian carcinoma cell line was obtained from theEuropean Collection of Cell Cultures (catalogue number 93112519,Salisbury, U.K.). All cell culture media were purchased from LifeTechnologies (Zug, Switzerland). A2780 cells were cultured in RPMI-1640medium (Gibco, GlutaMax), while MDA-MB-231 and HEK293 cells werecultured in Dulbecco's Modified Eagle Medium (DMEM, Gibco, GlutaMax)supplemented with 10% fetal bovine serum (FBS, Sigma-Aldrich, Buchs,Switzerland) and 1% penicillin/streptomycin (Life Technologies, Zug,Switzerland). MCF-10A were cultured in DMEM/F12 medium containing 10%horse serum and 1% antibiotics, supplemented with 10 μg/mL insulin, 20μg/mL hydrocortisone, 20 ng/mL epidermal growth factor and 100 ng/mLcholera toxin (all from Sigma Aldrich, Buchs, Switzerland). Cells wereincubated in a CO₂ incubator with 5% CO₂ and 100% relative humidity at37° C. MTT (MTT=3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazoliumbromide) was purchased from Calbiochem (Zug, Switzerland). Cellviability was determined by the MTT assay. The absorption was read usinga SpectraMax M52 microplate reader (Molecular Devices, Sunnyvale,Calif., USA).

Cells were seeded in 96-well plates as monolayers with 100 μL of cellsuspension (approximately 5000 cells) per well and preincubated for 24 hin medium supplemented with 10% FBS. With the exception of dacarbazine,all compounds were dissolved in DMSO. In the case of dacarbazine, anaqueous stock solution of the monocitrate was prepared in situ andimmediately used (light sensitivity). The stock solutions were seriallydiluted in the culture medium to the appropriate concentration, to givea final DMSO concentration of no higher than 0.5%. 100 μL of thecompound solution was added to each well, and the plates were incubatedfor 72 h. Subsequently, MTT (5 mg/mL solution) was added to the cellsand the plates were incubated for a further 2 h. The culture medium wasaspirated and the purple formazan crystals formed by the mitochondrialdehydrogenase activity of vital cells were dissolved in DMSO. Theoptical density, directly proportional to the number of surviving cells,was quantified at 590 nm using a multiwell plate reader, and thefraction of surviving cells was calculated from the absorbance ofuntreated control cells. Evaluation is based on means from at least twoindependent experiments, each comprising triplicates per concentrationlevel.

TABLE 1 IC50 values (μM) of selected triazenes after 72 h exposure onhuman ovarian cancer cells (A2780), human invasive breast cancer cells(MDA-MB-231), non-cancer human embryonic kidney cells (HEK293) and humanmammary epithelial cells (MCF-10A). MDA-MB- compound A2780 231 HEK293MCF-10A SC^(a) 1 56 ± 4 >500  44 ± 11 116 ± 2  — 2 160 ± 40 176 ± 60 125± 5  299 ± 43 1.7 4 32 ± 4  70 ± 10 29 ± 4 192 ± 12 2.7 5 22 ± 3 38 ± 319 ± 2  52 ± 11 1.4 6 143 ± 29 199 ± 21 165 ± 65 254 ± 52 1.2 9 20 ± 332 ± 4 14 ± 1 208 ± 49 6.5 10 34 ± 4 14 ± 2 21 ± 5 86 ± 4 6.1 14 43 ± 672 ± 9 24 ± 4 177 ± 23 2.5 15 47 ± 3  45 ± 15 15 ± 4 113 ± 7  2.4 ^(a)Sc≡ selectivity coefficient, IC₅₀ MCF-10A/IC₅₀ MDA-MB-231

1. A method for preparing a triazene according to Formula (I)

comprising reacting a compound according to Formula (II)R¹R²N(N₂O)M¹  Formula (II) with a compound according to Formula (III)R³M²  Formula (III) wherein R¹ and R² independently are an organicresidue R³ is an organic residue, M¹ is a metal compound, and M² is ametal compound.
 2. The method according to claim 1, wherein R¹ and R²are independently a substituted or unsubstituted aryl group, asubstituted or unsubstituted hetero aryl group, a substituted orunsubstituted alkyl group with 1 to 16 carbon atoms, a substituted orunsubstituted cyclic alkyl group with 3 to 12 carbon atoms, asubstituted or unsubstituted cyclic alkenyl group with 3 to 12 carbonatoms, a substituted or unsubstituted alkenyl group with 2 to 16 carbonatoms, or a substituted or unsubstituted alkynyl group with 2 to 16carbon atoms, wherein in the substituted or unsubstituted alkyl groupwith 1 to 16 carbon atoms, the substituted or unsubstituted cyclic alkylgroup with 3 to 12 carbon atoms, the substituted or unsubstituted cyclicalkyl group with 3 to 12 carbon atoms, the substituted or unsubstitutedalkenyl group with 2 to 12 carbon atoms, or the substituted orunsubstituted alkynyl group with 2 to 16 carbon atoms one or more —CH₂—group(s) are optionally substituted by —O—, —S—, —NR⁴—, or SiR⁴R^(4′) toform an ether, a thioether, a secondary or tertiary amine, or asilylether, and wherein R⁴ and R^(4′) are independently hydrogen, analkyl group with 1 to 6 carbon atoms or a cyclic alkyl group with 3 to 6carbon atoms or wherein R¹ and R² together with the nitrogen to which R¹and R² are attached form a hetero cycle with 3 to 7 carbon atoms.
 3. Themethod according to claim 1, wherein R³ is a substituted orunsubstituted aryl group, a substituted or unsubstituted hetero arylgroup, a substituted or unsubstituted alkyl group with 1 to 16 carbonatoms, a substituted or unsubstituted cyclic alkyl group with 3 to 12carbon atoms, a substituted or unsubstituted cyclic alkenyl group with 3to 12 carbon atoms, a substituted or unsubstituted alkenyl group with 2to 16 carbon atoms, or a substituted or unsubstituted alkynyl group with2 to 16 carbon atoms, wherein in the substituted or unsubstituted alkylgroup with 1 to 16 carbon atoms, the substituted or unsubstituted cyclicalkyl group with 3 to 12 carbon atoms, the substituted or unsubstitutedcyclic alkyl group with 3 to 12 carbon atoms, the substituted orunsubstituted alkenyl group with 2 to 12 carbon atoms, or thesubstituted or unsubstituted alkynyl group with 2 to 16 carbon atoms oneor more —CH₂— group(s) are optionally substituted by —O—, —S—, —NR⁴—, orSiR⁴R^(4′) to form an ether, a thioether, a secondary or tertiary amine,or silylether, and wherein R⁴ and R^(4′) are independently hydrogen, analkyl group with 1 to 6 carbon atoms or a cyclic alkyl group with 3 to 6carbon atoms.
 4. The method according to claim 1, wherein the compoundaccording to Formula (II)R¹R²N(N₂O)M¹  Formula (II) is prepared by reacting a compound accordingto Formula (IV)

with nitrous oxide.
 5. The method according to claim 4, comprisingreacting a compound according to Formula (IV) with a nitrous oxide and acompound according to Formula (III).
 6. A method for preparing acompound comprising a triazene group, wherein the method comprises areaction utilizing N₂O.
 7. The method according to claim 6 wherein acompound according to Formula(e) (I) and/or (II) is prepared.
 8. Acompound according to Formula (I)

wherein R¹ and R² are independently an organic residue and R³ is—C≡C—R⁵, wherein R⁵ is an organic residue; or R³ is —R⁶C═CR⁷R⁸, whereinR⁶, R⁷, and R⁸ are independently an organic residue and with the provisothat the C═C-bond is not part of an aromatic system.
 9. The compoundaccording to claim 8, wherein R⁵ is hydrogen, a trisubstituted silylgroup, a substituted or unsubstituted aryl group, a substituted orunsubstituted hetero aryl group, a substituted or unsubstituted alkylgroup with 1 to 16 carbon atoms, or a substituted or unsubstitutedcyclic alkyl group with 3 to 12 carbon atoms, wherein in the substitutedor unsubstituted alkyl group with 1 to 16 carbon atoms, the substitutedor unsubstituted cyclic alkyl group with 3 to 12 carbon atoms,optionally one or more —CH₂— group(s) can be substituted by —O—, —S—,—NR⁴—, or SiR⁴R^(4′) to form an ether, a thioether, a secondary ortertiary amine, or a silylether and wherein R⁴ and R^(4′) areindependently hydrogen or an alkyl group with 1 to 6 carbon atoms or acyclic alkyl group with 3 to 6 carbon atoms.
 10. The compound accordingto claim 8, wherein R⁶, R⁷ and R⁸ are independently hydrogen, atrisubstituted silyl group, a substituted or unsubstituted aryl group,or a substituted or unsubstituted hetero aryl group, or a substituted orunsubstituted alkyl group with 1 to 16 carbon atoms, or a substituted orunsubstituted cyclic alkyl group with 3 to 12 carbon atoms, wherein inthe substituted or unsubstituted alkyl group with 1 to 16 carbon atoms,the substituted or unsubstituted cyclic alkyl group with 3 to 12 carbonatoms, one or more —CH₂— group(s) can be substituted by —O—, —S—, —NR⁴—,SiR⁴R^(4′) to form an ether, a thioether, a secondary or tertiary amine,or a silylether and wherein R⁴ and R^(4′) are independently hydrogen, analkyl group with 1 to 6 carbon atoms or a cyclic alkyl group with 3 to 6carbon atoms, or wherein R⁶ and R⁷ or R⁶ and R⁸ together with the —C═C—double bond to which R⁶ and R⁷ or R⁶ and R⁸ are attached form a cyclicalkenyl group or a cyclic hetero alkenyl group and the remaining R⁷ orR⁸ is defined as above.
 11. A method for treating carcinosis comprisingadministering to a subject in need thereof a therapeutically effectiveamount of the compound according to claim
 8. 12. (canceled)
 13. Acompound according to Formula (II)R¹R²N(N₂O)M¹  Formula (II) wherein R¹ and R² independently are anorganic residue, and M¹ is a metal compound.
 14. A compound according toclaim 13, wherein the compound is present in isolated form.
 15. A methodfor preparing a compound according to Formula (II)R¹R²N(N₂O)M¹  Formula (II) by reacting R¹R²N-M¹ with nitrous oxide,wherein R¹ and R² independently are an organic residue, and M¹ is ametal compound.
 16. The method according to claim 1, wherein M¹ is ametal compound selected from the group consisting of Li, Na, and K. 17.The method according to claim 1, wherein M² is a metal compound selectedfrom the group consisting of Li, Na, K, MgCl, MgBr, MgI, ZnCl, ZnBr,ZnI, ZnR^(3′), and AlR^(3′)R³″, wherein R^(3′) and R³″ are independentlyan organic residue.
 18. The compound according to claim 13, wherein M¹is a metal compound selected from the group consisting of Li, Na, and K.19. The compound according to claim 14, wherein the compound is presentin isolated crystalline form.
 20. The method according to claim 15,wherein M¹ is a metal compound selected from the group consisting of Li,Na, and K.